Benzimidazole anthelmintics

ABSTRACT

PCT No. PCT/EP92/01578 Sec. 371 Date Jan. 14, 1994 Sec. 102(e) Date Jan. 14, 1994 PCT Filed Jul. 13, 1992 PCT Pub. No. WO93/02058 PCT Pub. Date Feb. 4, 1993This invention is directed to anthelmintic benzimidazole compounds of the formula (I),    &lt;IMAGE&gt;  (I)  wherein R1 is C1-C6 alkylthio; R2 is C1-C4 alkyl; and R3 is C1-C4 alkyl.

This application is a 371 of PCT/EP92/01578 filed Jul. 13, 1992.

The present invention related to certain benzimidazole anthelminticagents which, quite unexpectedly, are topically and parenterally activeand are thus suitable for transdermal and parenteral (especiallyintramuscular) administration.

These benzimidazole derivatives are represented by the followingformula: ##STR2## and their non-toxic salts, wherein R¹, which is in the5- or 6- position, is either (i) benzoyl, phenyloxy, phenylthio,phenylsulfinyl, phenylsulfonyl, phenylsulfonyloxy, C₁ -C₆ alkyl, C₁ -C₆alkoxy, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl or(C₃ -C₇ cycloalkyl) carbonyl, said phenyl groups, and the phenyl portionof said benzoyl group, optionally having 1 to 3 substituents eachindependently selected from halo, C₁ -C₄ alkyl, halo-(C₁ -C₄ alkyl), C₁-C₄ alkoxy, C₁ -C₄ alkylthio, C₁ -C₄ alkylsulfinyl, C₁ -C₄alkylsulfonyl, C₂ -C₄ alkanoyl, nitro, isothiocyanato, and cyano; or(ii) a group of the formula: ##STR3## where X is O,S,SO,SO₂ or NR⁴ inwhich R⁴ is hydrogen, C_(1-C) ₄ alkyl, phenyl or phenyl-(C₁ -C₄ alkyl),said phenyl groups being optionally substituted by 1 or 2 substituentseach selected from C₁ -C₄ alkyl, halo, hydroxy and C₁ -C₄ alkoxy; and R⁵is H, C₁ -C₄ alkyl, halo, hydroxy or C₁ -C₄ alkoxy; ##STR4##

R² is C₁ -C₄ alkyl; and R³ is C₁ -C₄ alkyl.

It will be appreciated that since in the compounds (I) the position ofthe hydrogen atom in the imidazole ring cannot be determined(tautomerism), then the compounds are correctly named as5(6)-substituted benzimidazoles.

R¹ is preferably C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkylthio, C₁ -C₄alkylsulphinyl, phenylthio, phenylsulfinyl, benzoyl optionallysubstituted by halo, phenylsulfonyloxy optionally substituted by halo,or 1,2-benzisoxazol-3-yl.

More preferably, R¹ is benzoyl, 4-fluorobenzoyl,4-fluorophenylsulfonyloxy, n-propylthio, n-propylsulfinyl, phenylthio,phenylsulfinyl, n-butyl, n-propyloxy, or 1,2-benzisoxazol-3-yl.

Most preferably, R¹ is n-propylthio or n-propylsulfinyl.

R² is preferably methyl or ethyl, most preferably methyl.

R³ is preferably methyl or ethyl, most preferably methyl.

Alkyl and alkoxy groups of 3 or more carbon atoms may be straight orbranched chain. "Halo" means F, Cl, Br or I.

Suitable non-toxic acid addition salts, suitable for veterinary use, arefor example the hydrochloride, hydrobromide, and sulphate salts. Thesecan all be prepared conventionally.

The benzimidazoles of the formula (I) and their salts are in particularanthelmintics suitable for the control of parasitic diseases in bothhuman and non-human animals such as sheep and cattle and domestic pets.The compounds exhibit activity against mature and immature parasiticforms of, for example, nematodes, trematodes and cestodes such as arerepresented by Trichostrongylus, Dictyocaulus, Ostertagia, Nematodirus,Stronglyoides, Trichuris, Haemonchus, Cooperia, Dirofilaria, Toxocara,Trichuris, Fasciola and Monezia species.

Efficient control of these species is achieved by introducing into saidanimals circulatory system an anthelmintically-effective amount of acompound (I) or salt thereof. In the case of these compounds, it hasbeen unexpectedly found that this control can be achieved bypercutaneous absorption and/or penetration from a liquid or creamformulation applied directly to the animals' skin. Such liquidformulations are known as "pour-on formulations". Such pour-onformulations are characterised in that the active ingredient, i.e. thecompound (I) or salt thereof, is dissolved, emulsified or suspended in asuitable solvent or solvent mixture which is tolerable by the skin andnon-toxic to the animal, optionally with certain auxiliary ingredients.

To prepare pour-on formulations, the compounds of the formula (I) andtheir salts are formulated in a conventional manner by mixing them withcarriers which are effective in penetrating the skin, the compound (I)then being absorbed by the animal through the skin and transmittedsystemically throughout the animal.

The pour on formulation contains:

1. a non volatile drug solvent or solvent mixture which may includesolvents normally classed as transdermal penetration enhancers, and,optionally, one or more of the following:

2. a solvent with the specific role of enhancing transdermal penetrationif such a solvent is not already present performing function 1 as themain drug solvent;

3. an accessory spreading agent if this auxiliary function is notperformed adequately by the drug solvent (1) and any transdermalpenetration enhancer (2);

4. a volatile solvent. This volatile solvent may aid the spreading anddistribution of components 1 and 2, adjust the formulation to aconvenient dosing volume, and ensure solubility and miscibility of theformulation in extreme storage conditions; and

5. further adjuvants, where necessary; to ensure chemical stability instorage and use, to increase the viscosity of the formulation to preventrun off, to deter other animals from licking the composition off thetreated animal, and to protect the skin from undesirable irritation.

Suitable drug solvents (1) are selected to achieve adequate solubilityfrom:

    ______________________________________                                        Spreading oils -                                                                             silicone oils, isopropyl                                                      myristate, isopropyl palmitate,                                               caprylic/capric acid                                                          triglyceride, saturated                                                       triglycerides of naturally                                                    occuring fatty acids, fatty                                                   acid esters (e.g. ethyl                                                       oleate), and fatty acid esters                                                which correspond to synthetic                                                 anatine uropygial gland fat.                                   Aliphatic hydrocarbons -                                                                     e.g. light paraffin oil.                                       Hydroxylic solvents -                                                                        less volatile alcohols (e.g.                                                  hexanol, octanol), propylene                                                  glycol, polypropylene glycols,                                                ethylene glycol, diethylene                                                   glycol, glycerols and ether and                                               or ester substituents of these                                                solvents, (e.g. Triacetin),                                                   aromatic alcohols such as                                                     benzyl alcohol and carboxylic                                                 acid esters (e.g. benzyl                                                      benzoate), butyl acetate,                                                     propylene carbonate and ethyl                                                 lactate.                                                       Polyalkoxylated solvents -                                                                   Polyethylene glycols,                                                         polyglycol ethers and or esters                                               e.g. 2-(2-alkoxy)ethoxyethanols                                               and 2-(2 alkoxy)ethoxyethyl                                                   alkanoates.                                                    Vegetable oils -                                                                             not included in the definition                                                of spreading oils e.g. corn,                                                  sesame, olive, pine, linseed,                                                 cottonseed and ground nut oil.                                 Penetration enhancing                                                                        (a) e.g. dimethylsulphoxide,                                   agents (2) -   dimethylformamide and                                                         dimethylacetamide;                                                            (b) Pyrrolidones. In                                                          particular 2-pyrrolidone, N-                                                  methylpyrrolidone,                                                            and 1 or 5 and 1,5 alkyl                                                      substituted pyrrolidones e.g.                                                 1.5-dimethyl-2-pyrrolidone or                                                 carboxylic acid substituted                                                   pyrrolidones; (c) alkylsulph-                                                 oxides, sugar esters and                                                      phosphine oxides; and (d)                                                     azacycloalkan-2-ones.                                          ______________________________________                                    

Where these solvents may be used in miscible combinations, miscibilitymay be achieved by incorporation of a ternary solvent if required, toprovide adequate drug solubility.

Accessory spreading agents (3) comprising spreading oils (if these arenot used as the main drug solvent as previously listed in (1)) orsurface active agents where the term surface active agent is used tocover materials variously called wetting agents, emulsifying agents anddispersing agents. These include:

Non-ionic water soluble emulsifiers such as alkylaryl polyglycol ethers,polyoxyethylene alkylaryl ether, alkylpolyglycol ethers, polyoxyethyleneesters and ethers, polyoxyethylene sorbitan mono fatty acid esters,sorbitan mono fatty acid esters, ethoxylated nonyl phenols,isooctylphenol, polyethoxyethanol and polyethoxylated castor oil(Cremophor EL^(R)). Anionic surfactants including soaps, fatty sulphateesters (e.g. dodecyl Na sulphate), fatty aromatic sulphonates (e.g.alkylbenzenesulphonates) more complex fatty sulphonates such as theamide condensation product of oleic acid and N-methyltaurine, the sodiumsulphonate of dioctylsuccinate and the disodium ethoxylated nonylphenolhalf ester of sulphosuccinic acid. Cationic agents such ascetyltrimethylammonium bromide may also be used as well as ampholyticsurfactants such as di-Na-N-lauryl betaiminodiopropionate or lecithin.Suitable volatile solvents (4) include: Ketones such as acetone, methylethyl ketone, methyl isobutyl ketone and cyclohexanone;

simple alcohols (in particular methanol, ethanol and [especially]isopropyl alcohol);

straight and branched alkyl ethers (e.g. dibutyl diisopropyl ether),tetrahydrofuran, glycol ethers and straight and branched chain alkylacetates (e.g. isopropyl acetate) and other esters such as lactic acidethyl ester;

aromatic hydrocarbons such as xylene, benzene, toluene,alkylnaphthalenes and chlorobenzenes; and

aliphatic hydrocarbons such as paraffins of chain length 6-20 andhalogenated aliphatic hydrocarbons.

Appropriate auxiliary additives (5) include:

    ______________________________________                                        Stability enhancers -                                                                      antioxidants e.g. ascorbic acid,                                              butyrated hydroxyanisole and                                                  butylated hydroxytoluene.                                        Colorants -  inorganic pigments, iron (II)                                                 oxide, titanium dioxide, Prussian                                             blue; organic dyestuffs e.g.                                                  alizarin based, azo dye-based or                                              metal phthalocyanine-based                                                    dyestuffs.                                                       Adhesion promoters -                                                                       carboxymethylcellulose,                                                       methylcellulose and other cellulose                                           and starch derivatives,                                                       polyacrylates, alginates,                                                     gelatines, gum arabic,                                                        polyvinylpyrrolidone, copolymers of                                           methylvinyl ether and maleic                                                  anhydride, polyethylene glycols,                                              paraffins, oils and waxes,                                                    hydrogenated castor oil, lecithins                                            and synthetic phospholipids.                                     Oral deterrents -                                                                          such as bitter aloes.                                            Emolients -  such as lanolin.                                                 ______________________________________                                    

The drug is dissolved in typical formulations which contain 1-100% ofthe main drug solvents, usually not more than 70% and ideally not morethan 20%. The rest of the formulation is composed in the main by thevolatile solvent which may comprise 0-99% of the formulation andpreferably not less than 30%. Further transdermal penetration enhancers(0-33%), accessory spreading agents (0-25%) and adjuvants (0-5%) areadded as required.

Preferred formulations for the actives were selected from typicalformulations.

Examples of some typical formulations are:

    ______________________________________                                        Ingredient           % Composition                                            ______________________________________                                        Formulation 1                                                                 2-(2-Butoxyethoxy)ethanol                                                                          100                                                      Formulation 2                                                                 2-(2-Butoxyethoxy)ethanol                                                                          5                                                        Propan-2-ol          95                                                       Formulation 3                                                                 Ethyl oleate         50                                                       Isopropyl acetate    50                                                       Formulation 4                                                                 Dimethylsulphoxide   20                                                       Xylene               80                                                       Formulation 5                                                                 Cetyl 2-ethylhexanoate/stearyl                                                                     10                                                       2-ethylhexanoate blend                                                        Propan-2-ol          90                                                       Formulation 6                                                                 PEG 300              60                                                       iso-octylphenoxypolyethoxyethanol                                             e.g. Triton X-100 R  10                                                       Propan-2-ol          30                                                       Formulation 7                                                                 Propylene glycol     50                                                       Hydroxypropyl cellulose (MW 1 ×                                         10.sup.6 Dalton)     0.5                                                      e.g. Klucel HPC HF.sup.R                                                      Butylated hydroxyanisole                                                                           0.02% w/v                                                Ethanol              to 100%                                                  Formulation 8                                                                 Propylene glycol     5                                                        Sodium Erythrosine   0-0.01% w/v                                              Methanol             to 100%                                                  Formulation 9                                                                 Triacetin            60                                                       Isopropyl acetate    40                                                       ______________________________________                                    

The pour-on formulations typically contain the active compound (I) saltthereof in an amount of from 0.5% wt/vol to 60% wt/vol. A typicalpour-on formulation would contain 1 to 50 mg of the active ingredientper kg of animal body weight in say, 0.01-1 ml per kg body weight of theanimal. Typically the formulation is simply poured on the animal.Concentrated formulations are often referred to as "spot-on"formulations, which are spotted onto the animal.

The compounds of formula (I) are administered as a formulationappropriate to the specific use envisaged and to the particular speciesof host animal being treated and the parasite involved. For use as ananthelmintic the compounds may be administered orally in the form of acapsule, bolus, tablet or drench or as a pour-on formulation, oralternatively, they can be administered by injection (e.g.subcutaneously, intramuscularly or intravenously) or as an implant. Suchformulations are prepared in a conventional manner in accordance withstandard veterinary practice. Thus capsules, boluses or tablets may beprepared by mixing the active ingredient with a suitable finely divideddiluent or carrier additionally containing a disintegrating agent and/orbinder such as starch, lactose, talc, magnesium stearate etc. Oraldrenches are prepared by dissolving or suspending the active ingredientin a suitable medium. Injectable formulations may be prepared in theform of a sterile solution which may contain other substances, forexample, enough salts or glucose to make the solution isotonic withblood. Acceptable liquid carriers include the vegetable oils such assesame oil and the like, glycerides such as triacetin and the like,esters such as benzyl benzoate, isopropyl myristate and fatty acidderivatives of propylene glycol and the like, as well as organicsolvents such as pyrrolidone, glycerol formal and the like. Theformulations are prepared by dissolving or suspending the activeingredient in the liquid carrier such that the final formulationcontains from 0.5 to 60% by weight of the active ingredient. Theseformulations will vary with regard to the weight of active compounddepending on the species of host animal to be treated, the severity andtype of infection and the body weight of the host. For parenteral andoral administration, typical dose ranges of the active ingredient are1-50 mg per kg of body weight of the animal. Pour-on formulations havebeen previously described.

As an alternative the compounds may be administered with the animalfeedstuff and for this purpose a concentrated feed additive or premixmay be prepared for mixing with the normal animal feed.

The compounds of the invention are highly active antiparasitic agentshaving utility not only as anthelmintics, but as ectoparasiticides,insecticides, acaricides, antifungal agents and antiprotozoal agents.

Thus the compounds are effective in treating a variety of conditionscaused by endoparasites including, in particular, helminthiasis which ismost frequently caused by a group of parasitic worms described asnematodes, cestodes and trematodes and which can cause severe economiclosses in swine, sheep, horses and cattle as well as affecting domesticanimals and poultry. The compounds are also effective against othernematodes which affect various species of animals including, forexample, Dirofilaria, Toxocara, Ancylostoma, Dipylidium, Echinococcuus,and Taenia in dogs and various parasites which can infect humansincluding gastro-intestinal parasites such as Ancylostoma, Necator,Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris, Enterobiusand parasites which are found in the blood or other tissues and organssuch as filarial worms and the extra intestinal stages of Strongyloidesand Trichinella.

The compounds are also of value in treating ectoparasite infectionsincluding in particular arthropod ectoparasites of animals and birdssuch as ticks, mites, lice, fleas, blowfly, biting insects and migratingdipterous larvae which can affect cattle and horses.

The compounds are also insecticides active against household pests suchas the cockroach, clothes moth, carpet beetle and the housefly as wellas being useful against arthropod pests of stored grain and ofagricultural plants such as spider mites, aphids, caterpillars andagainst migratory orthopterans such as locusts.

For use as an insecticide and for treating agricultural pests thecompounds are applied as sprays, dusts, emulsions and the like inaccordance with standard agricultural practice.

The compounds of the formula (I) are preparable by the alkylation ofcompounds of the formula (II): ##STR5## where R¹ and R³ are as definedfor formula (I). Alkylation can be carried out according to conventionaltechniques, e.g. using a C₁ -C₄ alkyl halide or di(C₁ -C₄ alkyl)sulphateand preferably in the presence of a base: the use of a C₁ -C₄ alkyliodide is preferred. Typical bases are potassium carbonate, sodiumcarbonate, triethylamine and n-butyllithium. Potassium carbonate is thepreferred base. The reaction is typically carried out in an organicsolvent such as dimethylformamide at about room temperature. Thepreferred solvent when using n-butyllithium is however tetrahydrofuran,and the reaction is then preferably carried under reflux.

The starting materials of the formula (II) are known compounds and anumber of them are known by generic non-proprietory names, as follows:##STR6##

For further details of the compounds (II) please also see for examplethe following references:

Sharma et.al., Proc. Drug. Res., 1983, 26, 85;

O. W. Ostmann et.al., Prog. Antimicrob. Anticancer Chemother, 1969, 1,159;

A. H. M. Raeymaekers, Arzneim-Forsch/Drug. Res., 28(1), 586;

E. A. Averkin et.al., J. Med. Chem, 1975, 18, 1164;

S. Ram et.al., Org. Prep. Proced. Int, 1985, 17, 215;

H. D. Brown et.al., JAGS, 1961, 83, 1764;

D. R. Hoff et.al., Experientia, 1970, 26, 550;

U.S. Pat. No. 3010968, GB 1123317; U.S. Pat. No. 3915986; U.S. Pat. No.4002640;

U.S. Pat. No. 4435418; U.S. Pat. No. 4826841; U.S. Pat. No. 4032536;U.S. Pat. No. 4512998;

DE-A-3247615; EP-A-0387941; EP-A-0009174; and ZA-7902975.

C₁ -C₆ alkylthio groups represented by R¹ can be oxidized to C₁ -C₆alkylsulfinyl and alkylsulfonyl groups by conventional techniques, e.g.by the use of 1 or more equivalents of m-chloroperbenzoic acid, asappropriate, in a suitable solvent such as methylene chloride.

The utility of the compounds as anthelmintics when given transdermallycan, for example, be assessed by the following technique:

Hale Cobb-Wistar rats weighing 40-50 g (3-4 weeks old) are used. Theanimals are fed on normal cubed rodent diet containing 60 ppm of theimmunosuppressant hydrocortisone acetate. Immunosuppression commencesone week prior to infection and is maintained until necropsy. Both foodand water are given ad lib.

Each rat is given 1500 T. colubriformis infective larvae orally.Ovine-derived larvae are prepared from stock cultures immediately beforedosing and checked microscopically for viability. Only motile, viablelarvae are used. Parasites are administered in 0.25 ml of water.

One to three weeks post-infection animals are randomly assigned toeither treatment (generally 5 rats) or control (generally 10 rats)groups. Solutions of test compounds in appropriate vehicles (see below)are administered topically by pipette to a shaven area (approximately 1square inch) of the back close to the neck. Drug concentrations in thevehicle are adjusted such that each animal receives the desired dosagein <0.25 ml/100 g body weight. At the time of dosing the weight of theanimals ranges from 90 to 110 g. All animals are necropsied three dayspost-dosing.

At necropsy the small intestine of each animal is removed and placed ina plastic pot containing 20 ml of pepsin digest mixture, comprisingpepsin A powder 8 g, NaCl 8.5 g, plus 16 ml concentrated HCl in 1 L ofdistilled water. The digests are incubated at 37° C. for 4 hours priorto washing over a 75 um sieve with a high pressure water spray. Wormsretained on the sieve are collected by washing into fresh pots andstained using an iodine/potassium iodide solution comprising iodine 30g, potassium iodide 40 g, plus 30 ml methylated spirits in 70 mldistilled water. The contents of each pot is then diluted to a finalvolume of 500 ml with distilled water and a 50 ml aliquot taken for wormcounting. The efficacy of each drug treatment is determined as thepercent reduction from the average worm burden of untreated controls.

The following Examples illustrate the preparation of the compounds ofthe formula (I) and formulations containing them.

EXAMPLE 1 Preparation of2-(N-methyl-N-[methoxycarbonyl]amino)-5(6)-n-propylthio-benzimidazole##STR7##

A mixture of methyl 5(6)-n-propylthio-benzimidazole-2carbamate, alsoknown by the generic name albendazole, (2.12 g, 0.008M), methyl iodide(1.16 g, 0.008M), potassium carbonate (1.1 g, 0.008M) anddimethylformamide (40 ml) was stirred at room temperature for two days,after which the solvent was evaporated. The residue was partitionedbetween ethyl acetate and water. The aqueous layer was separated andre-extracted with ethyl acetate. The combined organic layers were washedwith water, dried (MgSO₄) and evaporated. The crude product was purifiedby column chromatography on silica gel ("Silica gel 60", Merck [TradeMark], 100 g) eluting initially with dichloromethane and then withdichloromethane containing 0.5% methanol. Combination and evaporation ofappropriate fractions gave2-(N-methyl-N-[methoxycarbonyl]amino)-5(6)-n-propylthio-benzimidazole(1.3 g, 58%), m.p. 86°-88° C.

Analysis

Found: C,55.97%; H,6.15%; N,15.06%; C₁₃ H₁₇ N₃ O₂ S requires: C,55.89%;H,6.13%; N,15.04%.

EXAMPLES 2-9

The following compounds were prepared by the method of Example 1 fromthe appropriate benzimidazole starting material and alkyl iodide.##STR8##

    __________________________________________________________________________                            Elemental Analysis                                    Example No.                                                                          R.sup.1      R.sup.2                                                                           Calculated Found      M.P.                            __________________________________________________________________________                        Me  C, 52.87%; H, 5.80%; N, 14.23%                                                           C, 52.54%; H, 5.60%; N,                                                                  174-177° C.              3                                                                                     ##STR9##    Me  C, 50.66%; H, 3.72%; N, 11.08%                                                           C, 50.48%; H, 3.61%; N,                                                                  146-148° C.              4      O(CH.sub.2).sub.2 CH.sub.3                                                                 Me  C, 59.30%; H, 6.51%;                                                                     C, 59.13%; H, 6.35%;                                                                     133-134° C.                                      N, 15.96%  N, 15.69%                                  5      COPh         Me  C, 66.01%; H, 4.89%;                                                                     C, 65.78%; H, 4.92%;                                                                     181-182° C.                                      N, 13.58%  N, 13.43%                                  6      (CH.sub.2).sub.3 CH.sub.3                                                                  Me  C, 64.35%; H, 7.33%;                                                                     C, 64.35%; H, 7.26%;                                                                     115-116° C.                                      N, 16.08%  N, 16.26%                                  7      SPh          Me  C, 61.32%; H, 4.82%;                                                                     C, 61.29%; H, 4.75%;                                                                     136-138° C.                                      N, 13.41%  N, 13.55%                                  8      S(CH.sub.2).sub.2 CH.sub.3                                                                 Et  C, 57.32%; H, 6.53%;                                                                     C, 57.52%; H, 6.77%;                                                                     82-83° C.                                        N, 14.32%  N, 14.40%                                  9      S(CH.sub.2).sub.2 CH.sub.3                                             iPr    C, 58.61%; H, 6.89%;                                                                       C, 58.86%; H, 6.92%;                                                              Oil                                                                           N, 13.67%  N, 13.36%                                  __________________________________________________________________________

EXAMPLE 10

A composition suitable for transdermal administration is as follows:

    ______________________________________                                        The product of Example 1 0.158 g                                              2-(2-Butoxyethoxy)ethanol                                                                              0.265 g                                              2-Pyrrolidone            0.311 g                                              Isopropyl acetate        0.242 g                                                                       0.976 g                                              ______________________________________                                    

EXAMPLE 11

A composition suitable for sub-cutaneous administration is as follows:

    ______________________________________                                        Compound of Example 1 0.075    g                                              Sesame oil            0.333    ml                                             Benzyl benzoate       0.333    ml                                             Ethyl oleate          0.333    ml                                                                   (Total 1 ml)                                            ______________________________________                                    

We claim:
 1. A benzimidazole derivative of the formula: ##STR10## or a non-toxic salt thereof, wherein R¹, which is in the 5- or 6- position, is C₁ -C₆ alkylthio;and R² and R³ are each independently C₁ -C₄ alkyl.
 2. A compound as claimed in claim 1 in which R¹ is n-propylthio.
 3. A compound as claimed in claim 1 in which R² is methyl or ethyl.
 4. A compound as claimed in claim 3 in which R¹ is n-propylthio.
 5. A compound as claimed in claim 4 in which R² is methyl.
 6. A compound as claimed in claim 1 in which R³ is methyl or ethyl.
 7. A compound as claimed in claim 6 in which R¹ is n-propylthio.
 8. A compound as claimed in claim 7 in which R² is methyl.
 9. A compound as claimed in claim 8 in which R³ is methyl.
 10. A compound as claimed in claim 1 in which R¹ is n-propylthio, R² is methyl and R³ is methyl.
 11. An anthelmintic composition comprising a compound according to claim 1 or a non-toxic salt thereof together with a diluent or carrier.
 12. A composition as claimed in claim 11 which is in a form suitable for transdermal, oral or parenteral administration.
 13. A method of combating helminths in an animal, which comprises applying to the skin of the animal in an amount sufficient to exert an anthelmintic effect, an anthelmintic composition comprising a compound according to claim 1 or a non-toxic salt thereof carrier effective for passing said compound or salt thereof through the skin of the animal.
 14. A method of combating helminths in an animal, comprising administering orally or parenterally to said animal an anthelmintically-effective amount of a compound according to claim 1 or salt thereof. 